JP2023543267A - Drug implant containing apalutamide and method of use thereof - Google Patents

Abstract

Provided herein is a drug implant comprising apalutamide for the treatment of a disease in a subject. In some cases, the drug implant may include a polymer matrix and apalutamide disposed therein. Further provided are methods for manufacturing drug implants and methods for treating diseases with implants. In some cases, drug implants may be used to treat proliferative diseases of the prostate. [Selection diagram] Figure 1A

Description

CROSS-REFERENCE This application claims the benefit of U.S. Provisional Patent Application No. 63/084,450, filed September 28, 2020, which is incorporated herein by reference in its entirety.

The burden of prostate cancer in the United States is significant. In 2009, approximately 192,000 men were expected to be diagnosed with prostate cancer and 27,000 men would die from the disease. Approximately 2.2 million living American men have been diagnosed with prostate cancer, and some live with metastatic, painful, and functionally limiting disease. Prostate cancer is by far the most commonly diagnosed cancer among American men and remains the second leading cause of cancer death in men. Hormone therapy for prostate cancer includes a wide variety of treatments designed to affect cells whose normal function depends on androgens, including testosterone and dihydrotestosterone, among others. Prostate cancer cells are generally highly sensitive to treatments that reduce androgen levels or affect the normal functioning of these hormones.

Apalutamide is an antiandrogen that can be used to treat prostate cancer. Apalutamide is a member of the nonsteroidal antiandrogen (NSAA) family of medicines and works by blocking androgen receptors. Apalutamide has been associated with some side effects that may be due in part to the relatively large doses of apalutamide that are administered systemically to obtain therapeutic benefit. Therefore, local administration of smaller amounts of apalutamide may be able to achieve therapeutic benefits and prevent or reduce the side effects or toxicity of systemic administration of apalutamide.

There is a need for improved drug implants that can be used to deliver therapeutically active agents (eg, apalutamide) directly to target tissues of a subject. This disclosure fills this unmet need.

In one embodiment, a drug implant comprising a mixture of a non-biodegradable, non-bioabsorbable, and/or non-bioerodible polymer and apalutamide, wherein the drug implant is implanted in a subject and the apalutamide is applied to a desired treatment site. A drug implant is provided that is configured to release a drug. In some cases, the drug implant is configured to release a therapeutically effective amount of apalutamide to the desired treatment site. In some cases, the drug implant is configured to release a therapeutically effective amount of apalutamide to the desired treatment site for at least 3 months. In some cases, the drug implant is configured to release a therapeutically effective amount of apalutamide to the desired treatment site for at least 6 months. In some cases, the drug implant is configured to release a therapeutically effective amount of apalutamide to the desired treatment site for up to two years. In some cases, the cumulative release of apalutamide in the in vitro model is 2,000 μg or less by day 1, 10,000 μg or less by day 60, and/or 12,000 μg or less by day 120, and At least 10 μg by day 1, at least 100 μg by day 60, and/or at least 150 μg by day 120, and the in vitro model is 1% sodium dodecyl sulfate in water with continuous stirring at 37 °C Incubating the drug implant in (SDS). In some cases, the drug implant releases at least 0.1 micrograms/day of apalutamide six months after implantation in the subject. In some cases, at least 50% of the total apalutamide remains in the drug implant 100 days after implantation into the subject. In some cases, apalutamide is present in the drug implant in an amount of at least 10% w/w. In some cases, apalutamide is present in the drug implant in an amount of at least 30% w/w. In some cases, apalutamide is present in the drug implant in an amount of at least 50% w/w. In some cases, apalutamide is present in the drug implant in an amount of at least 70% w/w. In some cases, apalutamide is present in the drug implant in an amount of 10% to 70% w/w. In some cases, the drug implant has a Shore A hardness of at least 25 durometers when loaded with 10% apalutamide. In some cases, the non-biodegradable, non-bioabsorbable, and/or non-bioerodible polymer includes silicone. In some cases, the silicone is an acetoxy cured silicone. In some cases, the non-biodegradable, non-bioabsorbable, and/or non-bioerodible polymer includes thermoplastic polyurethane (TPU). In some cases, the total amount of apalutamide in the drug implant is about 1 mg to about 20 mg. In some cases, the non-biodegradable, non-bioabsorbable, and/or non-bioerodible polymer is biocompatible. In some cases, at least 99% of the non-biodegradable, non-bioabsorbable, and/or non-bioerodible polymer is configured to remain in the subject's target tissue for at least 600 days after implantation. There is. In some cases, apalutamide is in solid form. In some cases, at least a portion of the apalutamide is in crystalline form. In some cases, the drug implant is visible by ultrasound when placed in the target tissue of the subject. In some cases, apalutamide has a melting temperature that is higher than the molding or curing temperature of the non-biodegradable, non-bioabsorbable, and/or non-bioerodible polymer. In some cases, the drug implant inhibits modulation of apalutamide within the drug implant. In some cases, modulation includes decomposition. In some cases, drug implants are elongated. In some cases, the drug implant is cylindrical. In some cases, the drug implant is tubular. In some cases, the drug implant is rod-shaped. In some cases, the diameter of the drug implant is about 0.1 mm to about 1.5 mm. In some cases, the length of the drug implant is about 1 mm to about 30 mm. In some cases, the volume of the drug implant is about 0.1 mm ³ to about 30 mm ³ . In some cases, at least 50% of the exterior surface of the drug implant is configured to directly contact the target tissue. In some cases, the desired treatment site is the prostate or prostate tissue. In some cases, drug implants are configured to be delivered to a subject using a needle or catheter lumen. In some cases, the drug implant lacks at least one of a sheath, a scaffold, a retention member to retain the drug implant within the target tissue, or a combination thereof. In some cases, the drug implant further includes a coating. In some cases, the coating partially covers the drug implant. In some cases, the coating substantially covers the drug implant. In some cases, the coating covers the drug implant. In some cases, the coating is biodegradable. In some cases, the coating is non-biodegradable. In some cases, drug implants are sterile. In some cases, the drug implant is disposed within a sterilizable package. In some cases, the drug implant consists essentially of non-biodegradable, non-bioabsorbable, and/or non-bioerodible polymers and apalutamide.

In another embodiment, a method of treating a proliferative disease of the prostate in a subject, the method comprising administering one or more drug implants according to any one of the foregoing to prostate tissue or tissue near the prostate of the subject. A method is provided that includes transplanting. In some cases, one or more drug implants deliver a therapeutically effective amount of apalutamide to the prostate for at least 3 months. In some cases, one or more drug implants deliver a therapeutically effective amount of apalutamide to the prostate for at least six months. In some cases, the proliferative disease of the prostate is prostate cancer or benign prostatic hyperplasia. In some cases, apalutamide is dispersed within a non-biodegradable, non-bioabsorbable, and/or non-bioerodible polymer prior to implantation. In some cases, implantation involves placing each of the one or more drug implants into prostate tissue or tissue near the prostate through the lumen of a needle or catheter. In some cases, implantation is performed by transperineal administration. In some cases, transperineal administration involves using a template guided needle. In some cases, the total dose of apalutamide administered to the subject is less than the total dose of apalutamide when administered to the subject by oral administration. In some cases, the total dose of apalutamide administered to a subject is less than 200 mg over a 6 month period. In some cases, transplantation results in a plasma concentration of apalutamide that is less than the plasma concentration of apalutamide obtained when apalutamide is administered to the subject by oral administration. In some cases, transplantation results in subtherapeutic steady-state plasma concentrations of apalutamide. In some cases, the one or more drug implants include 2-20 drug implants.

In another aspect, a kit is provided that includes a sterilizable package containing a drug implant according to any one of the foregoing and instructions for implanting the drug implant into a target tissue of a subject.

In another aspect, a drug implant is provided that includes a) a polymer matrix and b) apalutamide dispersed within the biocompatible polymer matrix. In some cases, apalutamide is present in the drug implant in an amount of at least about 10% w/w to about 80% w/w. In some cases, the total dose of apalutamide in the drug implant is about 1 mg to about 10 mg. In some cases, the drug implant releases at least about 0.5 μg/day of apalutamide 6 months after implantation in the subject. In some cases, the cumulative release of apalutamide in the in vitro model is at least one of the following: at least 15 μg on day 1, at least 120 μg on day 60, or at least 170 μg on day 120. In some cases, the polymer matrix is silicone. In some cases, the silicone is an acetoxy cured silicone. In some cases, the polymer matrix is a thermoplastic polyurethane. In some cases, at least 50% of the apalutamide remains in the polymer matrix 100 days after implantation. In some cases, the polymer matrix is biocompatible. In some cases, the polymer matrix is substantially non-biodegradable. In some cases, at least 99% of the polymer matrix remains in the subject's target tissue for at least 600 days after implantation. In some cases, apalutamide is in solid form. In some cases, apalutamide is in crystalline form. In some cases, the drug implant has a Shore A hardness of at least 20 durometers when loaded with 60% w/w therapeutically active agent. In some cases, the drug implant is visible by ultrasound when placed in the target tissue of the subject. In some cases, apalutamide has a melting temperature that is higher than the molding or curing temperature of the polymer matrix. In some cases, the drug implant inhibits modulation of apalutamide within the drug implant. In some cases, modulation includes decomposition. In some cases, drug implants are elongated. In some cases, the drug implant is cylindrical. In some cases, the drug implant is tubular. In some cases, the drug implant is rod-shaped. In some cases, the diameter of the drug implant is about 0.1 mm to about 1.5 mm. In some cases, the length of the drug implant is about 1 mm to about 30 mm. In some cases, the volume of the drug implant is about 0.1 mm ³ to about 30 mm ³ . In some cases, at least 50% of the exterior surface of the drug implant is configured to directly contact the target tissue. In some cases, the drug implant is configured to be implanted into the target tissue or tissue near or adjacent to the target tissue. In some cases, the target tissue is prostate tissue. In some cases, drug implants are configured to be delivered to the target tissue using a needle or catheter lumen. In some cases, the drug implant lacks at least one of a sheath, a scaffold, a retention member to retain the drug implant within the target tissue, or a combination thereof. In some cases, the drug implant further includes a coating. In some cases, the coating partially covers the drug implant. In some cases, the coating substantially covers the drug implant. In some cases, the coating covers the drug implant. In some cases, drug implants are sterile. In some cases, drug implants are placed in sterile packaging. In some cases, the drug implant consists essentially of a polymer matrix and apalutamide dispersed within the polymer matrix.

In another embodiment, a method of treating a proliferative disease of the prostate in a subject, the method comprising implanting one or more drug implants according to any one of the foregoing into prostate tissue or tissue near the prostate. A method is provided, comprising: In some cases, one or more drug implants deliver a therapeutically effective amount of apalutamide to the prostate for at least six months. In some cases, the proliferative disease of the prostate is prostate cancer or benign prostatic hyperplasia. In some cases, the prostate cancer is metastatic castration-sensitive prostate cancer or non-metastatic castration-resistant prostate cancer. In some cases, apalutamide is dispersed within a polymer matrix prior to implantation. In some cases, implantation involves placing each of the one or more drug implants into prostate tissue or tissue near the prostate through the lumen of a needle or catheter. In some cases, implantation is performed by transperineal administration. In some cases, transperineal administration involves using a template guided needle. In some cases, the total dose of apalutamide administered to the subject is less than the total dose of apalutamide when administered to the subject by oral administration. In some cases, the total dose of apalutamide administered to a subject is less than 100 mg over a six month period. In some cases, transplantation results in a plasma concentration of apalutamide that is less than the plasma concentration of apalutamide obtained when apalutamide is administered to the subject by oral administration. In some cases, transplantation results in steady state plasma concentrations of apalutamide of less than about 6 μg/mL. In some cases, the one or more drug implants include 2-8 drug implants.

In another embodiment, a method of manufacturing any one of the aforementioned drug implants, the method comprising: (a) mixing an amount of uncured polymer with an amount of apalutamide to form a mixture. (b) molding the mixture to produce a molding mixture; and (c) curing the molding mixture by heating the molding mixture for a period of time. In some cases, the amount of apalutamide is between 10% w/w and 70% w/w of the uncured polymer. In some cases, the polymer is a silicone or a thermoplastic polyurethane. In some cases, curing (c) further comprises heating the molding mixture at a temperature of about 150° C. to about 200° C. for about 3 to about 8 minutes. In some cases, the mixture further includes a solvent. In some cases, the solvent is selected from the group consisting of pentane, dichloromethane, tetrahydrofuran, heptane, toluene, and hexane. In some cases, the mixture is formed by a transfer molding process or by extrusion through a tube. In some cases, the method further includes performing the analysis on the drug implant. In some cases, analyzes include differential scanning calorimetry (DSC), placement of drug implants in tissue substitutes, dissolution studies, rheology, high pressure liquid chromatography (HPLC), simulated in vivo stability assays, and dynamic mechanical analysis (DMA). ) selected from the group consisting of

In another aspect, a sterile package comprising a drug implant according to any one of the preceding claims herein and instructions for implanting the drug implant into a target tissue of a subject. A kit is provided including:

The novel features of the disclosure are pointed out with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure may be gained by reference to the following detailed description and accompanying drawings that describe exemplary embodiments in which principles of the present disclosure are utilized.

2 shows the results of dissolution testing of exemplary drug implants of the present disclosure. 2 shows the results of dissolution testing of exemplary drug implants of the present disclosure. 2 shows the results of dissolution testing of exemplary drug implants of the present disclosure. FIG. 2 shows a differential scanning calorimetry (DSC) analysis of an exemplary drug implant of the present disclosure. FIG. 2 shows a differential scanning calorimetry (DSC) analysis of an exemplary drug implant of the present disclosure. 2 shows the results of dissolution testing of exemplary drug implants of the present disclosure. 2 shows the results of dissolution testing of exemplary drug implants of the present disclosure. 2 shows the results of dissolution testing of exemplary drug implants of the present disclosure. FIG. 2 shows a differential scanning calorimetry (DSC) analysis of an exemplary drug implant of the present disclosure. FIG. 2 shows a differential scanning calorimetry (DSC) analysis of an exemplary drug implant of the present disclosure. FIG. 2 shows a differential scanning calorimetry (DSC) analysis of an exemplary drug implant of the present disclosure. FIG. 2 shows a differential scanning calorimetry (DSC) analysis of an exemplary drug implant of the present disclosure.

Provided herein is a drug implant that can deliver a therapeutically effective amount of apalutamide directly to a target tissue. Further provided herein are drug implants that, when implanted into a target tissue, result in high concentrations of apalutamide within the target tissue and low concentrations of apalutamide in systemic circulation (eg, plasma). In some cases, the ability of the drug implants provided herein to deliver therapeutically effective amounts of apalutamide directly to target tissues may result in low (e.g., subtherapeutic) concentrations of apalutamide being achieved in the systemic circulation. However, side effects or toxicity of apalutamide treatment that would otherwise result from systemic administration can be reduced or eliminated. Additionally, direct delivery of apalutamide to the target tissue by the drug implants described herein ensures that the target tissue receives a therapeutically effective amount of apalutamide. In a further aspect, the drug implants provided herein can be loaded with large amounts of apalutamide such that the drug implant can sustainably release apalutamide to the target tissue over an extended period of time. In some embodiments, apalutamide may be dispersed within the polymeric matrix of the implant, which may provide certain advantages (eg, faster elution time, higher drug loading within the implant, etc.). In certain embodiments, the drug implants provided herein allow a therapeutically effective amount of apalutamide to be administered directly to prostate tissue for an extended period of time (e.g., for six months or more) while maintaining low systemic concentrations of apalutamide. As such, it may contain high concentrations of bicalutamide. In further particular embodiments, the drug implants provided herein are non-biodegradable, non-bioabsorbable, and/or non-biodegradable, such that the drug implant can remain in a subject indefinitely. May contain corrosive polymers.

In various embodiments, the drug implants disclosed herein can include a polymer matrix and apalutamide. In certain cases, apalutamide may be dispersed within a polymer matrix. The drug implant can be implanted into the target tissue and release a quantity of apalutamide over time. Drug implants containing apalutamide may be effective in treating the disease or its symptoms. The disease can be, for example, a proliferative disease of the prostate, such as prostate cancer or benign prostatic hyperplasia.

Further provided herein is a method of treating a disease by delivering a drug implant of the present disclosure to a target tissue of a subject in need thereof for long-term delivery of a therapeutically effective amount of apalutamide. . Further provided are methods of manufacturing drug implants and kits containing drug implants.

Drug Implants Provided herein are drug implants (also referred to herein as "implants" or "drug implants") suitable for delivering apalutamide to target tissues. In some embodiments of the present disclosure, the implant includes a polymer matrix and apalutamide dispersed therein. The implant may be suitable, for example, for treating proliferative diseases of the prostate, such as prostate cancer or benign prostatic hyperplasia.

The polymer matrix may include any polymeric material. Generally, polymeric materials are biocompatible. The term "biocompatible" as used herein refers to the properties of a material that allow for prolonged contact with tissue in a subject without causing toxicity or significant damage.

Generally, the polymeric materials used in the drug implants of the present disclosure are non-biodegradable, non-bioabsorbable, and/or non-bioerodible. In some embodiments, the polymeric material can be "non-biodegradable" or "substantially non-biodegradable." The terms "non-biodegradable" or "substantially non-biodegradable" when used with respect to an implant of the present disclosure generally are degraded by microorganisms over the intended life of the implant or over the life of a control. Refers to a polymeric material (eg, present within the implants of the present disclosure) that cannot be degraded or substantially degraded. For example, the substantially non-biodegradable implants of the present disclosure may have at least 99% of the polymeric material remaining two years after the device is implanted in the target tissue.

In some embodiments, the polymeric material can be "non-bioabsorbable." The term "non-bioresorbable" when used with respect to the implants of the present disclosure means that the polymeric material (e.g., present in the implants of the present disclosure) is not absorbed by the subject's body, such as cells or tissues. . In some embodiments, the polymeric material can be "non-bioerodible." The term "non-bioerodible" when used with respect to the implants of the present disclosure means that the polymeric material (e.g., present in the implants of the present disclosure) is not present in the surrounding tissue, in fluids, or by cellular action. means that it will not corrode or decompose over time upon contact with substances found by.

In certain embodiments of the present disclosure, the polymer matrix may include polysiloxane (silicone). The silicone can be any biocompatible silicone. In some cases, the silicone can be medical grade silicone. In some cases silicones can be hydrophobic. In some cases, the silicone can be a United States Pharmacopeia (USP) Class V or USP Class VI certified silicone. In various embodiments, the silicone can be an acetoxy cured silicone. In some cases, the silicone can be Silbione® silicone adhesive manufactured by Elkem (e.g., Silbione® Biomedical ADH1 M200, as of September 1, 2020, silicone.elkem/EN/ our_offer/Product/90061907/_/SILBIONE-BIO-ADH1-M200). Generally, silicones are non-biodegradable, non-bioabsorbable, and/or non-bioerodible.

In various other embodiments, the polymeric material can be a thermoplastic polyurethane. In some cases, the polyurethane can be one or more of the following polyurethanes manufactured by Lubrizol: PY-PT72AE, PY-PT87AE, PY-PT87AS, PY-PT83AL, and PY-PT43DE20 (as of September 18, 2020, lubrizol.com/-/media/Lubrizol/Life-Sciences/Document s/Literature/Pathway-Solvent -Effects-Testing.pdf). Generally, polyurethanes are non-biodegradable, non-bioabsorbable, and/or non-bioerodible.

In various other embodiments, the polymeric material can be poly(ethylene-vinyl acetate) (PEVA). In some cases, the PEVA can be VitalDose®, available from manufacturer Celanese.

The hardness of rubber is measured using the Shore A hardness scale. Higher numbers on the scale refer to harder materials, while lower numbers on the scale refer to softer materials. Generally, the polymeric material within the drug implant has a Shore A hardness of at least 25 durometers. For example, the polymeric material can have a Shore A hardness of at least 25 durometers, at least 30 durometers, at least 40 durometers, at least 50 durometers, at least 60 durometers, or at least 70 durometers. In one aspect, the uncured polymeric material can have a Shore A hardness of 30 durometers and the cured polymeric material can have a Shore A hardness of 70 durometers.

The implant may further include a therapeutically active agent (eg, apalutamide). In some cases, apalutamide is dispersed or distributed within the polymer matrix. In some cases, apalutamide is dispersed or distributed throughout the polymer matrix. In some cases, apalutamide is uniformly or homogeneously dispersed or distributed within the polymer matrix. In other cases, apalutamide is heterogeneously dispersed or distributed within the polymer matrix. In other cases, apalutamide is dispersed or distributed in a gradient manner within the polymer matrix. In certain embodiments, apalutamide is dispersed or distributed within the polymer matrix during manufacture of the implant (e.g., apalutamide is mixed with the polymeric material prior to curing of the polymeric material, as disclosed herein). ). In some cases, dispersing apalutamide within a polymer matrix may be advantageous over other drug implants, such as those in which the drug is encapsulated in a capsule or within the lumen of a tube. For example, dispersing the drug within a polymer matrix may allow for higher apalutamide loading in the implant, faster elution rates, etc.

In various embodiments of the present disclosure, the implant may include a therapeutically active agent (eg, apalutamide) in an amount of about 0.5% w/w to about 70% w/w. For example, the implant may be about 0.5% w/w, about 1% w/w, about 5% w/w, about 10% w/w, about 15% w/w, about 20% w/w, about 25% w/w, about 30% w/w, about 35% w/w, about 40% w/w, about 45% w/w, about 50% w/w, about 55% w/w, about 60 % w/w, about 65% w/w, or about 70% w/w. In various embodiments, the implant comprises at least about 0.5% w/w, at least about 1% w/w, at least about 5% w/w, at least about 10% w/w, at least about 15% w/w, at least about 20% w/w, at least about 25% w/w, at least about 30% w/w, at least about 35% w/w, at least about 40% w/w, at least about 45% w/w, at least about a therapeutically active agent (e.g., apalutamide) in an amount of 50% w/w, at least about 55% w/w, at least about 60% w/w, at least about 65% w/w, or at least about 70% w/w. may be included. In certain embodiments, apalutamide is about 0.5% w/w, about 1% w/w, about 5% w/w, about 10% w/w, about 30% w/w, about 45% w/w. w, present in the implant in an amount of approximately 60% w/w. In some cases, the present disclosure provides drug implants loaded with high concentrations of apalutamide (eg, about 60% w/w or more). In some cases, the implant may contain apalutamide in an amount of at least about 30% w/w. In some cases, the implant may contain apalutamide in an amount of at least about 45% w/w. In some cases, the implant may contain apalutamide in an amount of about 10% w/w or at least about 10% w/w.

In various embodiments of the present disclosure, the implant may include a therapeutically active agent (eg, apalutamide) in an amount of about 5% volume/volume (v/v) to about 60% v/v. For example, the implant may be about 5% v/v, about 10% v/v, about 15% v/v, about 20% v/v, about 25% v/v, about 30% v/v, about 35% v/v, about 40% v/v, about 45% v/v, about 50% v/v, about 55% v/v, or about 60% v/v of a therapeutically active agent (e.g., apalutamide) may include. In various embodiments, the implant has at least about 5% v/v, at least about 10% v/v, at least about 15% v/v, at least about 20% v/v, at least about 25% v/v, at least about 30% v/v, at least about 35% v/v, at least about 40% v/v, at least about 45% v/v, at least about 50% v/v, at least about 55% v/v, or at least about 60 % v/v of a therapeutically active agent (eg, apalutamide). In certain embodiments, apalutamide is present in the implant in an amount of at least about 30% v/v.

In various embodiments, implants of the present disclosure can include apalutamide in a total amount of at least about 1 mg, such as from about 1 mg to about 20 mg. In some cases, the total amount of apalutamide in the implant can be about 8 mg to about 10 mg. For example, the implant may be about 1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2 .0mg, about 2.1mg, about 2.2mg, about 2.3mg, about 2.4mg, about 2.5mg, about 2.6mg, about 2.7mg, about 2.8mg, about 2.9mg, about 3 .0mg, about 3.1mg, about 3.2mg, about 3.3mg, about 3.4mg, about 3.5mg, about 3.6mg, about 3.7mg, about 3.8mg, about 3.9mg, about 4 .0mg, about 4.1mg, about 4.2mg, about 4.3mg, about 4.4mg, about 4.5mg, about 4.6mg, about 4.7mg, about 4.8mg, about 4.9mg, about 5 .0mg, about 5.1mg, about 5.2mg, about 5.3mg, about 5.4mg, about 5.5mg, about 5.6mg, about 5.7mg, about 5.8mg, about 5.9mg, about 6 .0mg, about 6.1mg, about 6.2mg, about 6.3mg, about 6.4mg, about 6.5mg, about 6.6mg, about 6.7mg, about 6.8mg, about 6.9mg, about 7 .0mg, about 7.1mg, about 7.2mg, about 7.3mg, about 7.4mg, about 7.5mg, about 7.6mg, about 7.7mg, about 7.8mg, about 7.9mg, about 8 .0mg, about 8.1mg, about 8.2mg, about 8.3mg, about 8.4mg, about 8.5mg, about 8.6mg, about 8.7mg, about 8.8mg, about 8.9mg, about 9 .0mg, about 9.1mg, about 9.2mg, about 9.3mg, about 9.4mg, about 9.5mg, about 9.6mg, about 9.7mg, about 9.8mg, about 9.9mg, or about 10.0mg, about 10.5mg, about 11.0mg, about 11.5mg, about 12.0mg, about 12.5mg, about 13.0mg, about 13.5mg, about 14.0mg, about 14.5mg, about 15.0 mg, about 15.5 mg, about 16.0 mg, about 16.5 mg, about 17.0 mg, about 17.5 mg, about 18.0 mg, about 18.5 mg, about 19.0 mg, about 19.5 mg, or Apalutamide may be included in a total amount of about 20.0 mg.

In various embodiments of the present disclosure, the polymeric material can be cured with apalutamide present therein. Without wishing to be bound by theory, curing refers to a chemical process that hardens polymeric materials by crosslinking polymer chains. Any method can be used to cure the polymers of the present disclosure, including the use of electron beams, heating, and/or addition of additives. In various embodiments of the present disclosure, apalutamide may be mixed with uncured polymeric material prior to curing. In some embodiments, the polymer matrix can be at least 95% cured, at least 96% cured, at least 97% cured, at least 98% cured, at least 99% cured, at least 99.9% cured, or 100% cured.

Generally, the polymeric material has a molding or curing temperature that is lower than the melting temperature of apalutamide, for example, to prevent melting and/or degradation of the drug. In some cases, the polymeric material has a It may have a forming temperature or a curing temperature.

In some cases, the polymer is thermofusible or thermoplastic (eg, polyurethane), which becomes moldable at elevated temperatures and hardens upon cooling. In certain examples, apalutamide can have a melting temperature of about 190°C to about 192°C, and the polymer can have a molding or curing temperature of less than about 190°C (eg, about 170°C). In some cases, the polymer is a thermoset (eg, silicone) that is irreversibly cured by curing that can be facilitated by the addition of a catalyst and/or the addition of heat. In some cases, the polymeric material can be cured at room temperature (eg, about 25° C.). In some cases, polymers require exposure to air to cure.

In various embodiments of the present disclosure, apalutamide may be present in the implant in solid form. In some cases, solid apalutamide can dissolve upon contact with biological fluids (eg, after implantation into tissue) and can diffuse out of the implant and into the target tissue. In some cases, apalutamide is present in crystalline form in the implant. In general, the particle size of apalutamide within the implant can be important for uniformity of drug content within the implant. Without wishing to be bound by theory, small particle size may ensure uniform distribution within the formulation and between implants upon shaping of the formulation. In some cases, the apalutamide present in the implant can have a median particle size value (eg, D50 particle size) of less than about 10 μm. In some cases, the apalutamide present in the implant can have a D90 particle size of less than about 15 μm. In some cases, the apalutamide present in the implant is amorphous. In some cases, apalutamide recrystallizes in the implant after curing or cooling.

Generally, the implants of the present disclosure have mechanical properties that allow the implant to be successfully placed into target tissue. For example, the implant of the present disclosure can be sufficiently rigid so that it can be successfully placed into the target tissue, but not so stiff that it breaks during placement. It is to be understood that the mechanical properties of the devices described herein may vary depending on the polymeric material used and may be determined empirically. In some embodiments, an implant containing apalutamide can have a Shore A hardness of at least 25 durometers. In certain embodiments, the implant can have a Shore A hardness of at least 25 durometers when loaded with 10% w/w apalutamide.

In various embodiments, the implant can have a three-dimensional shape. The three-dimensional shape may be any suitable shape. In some cases, the implant can be cylindrical or substantially cylindrical. In some cases, the implant can be tubular or substantially tubular. In some cases, the implant may be elongated (eg, have a length greater than its width). In some cases, the implant may not be hollow. In some cases, the implant can be rod-shaped or rod-shaped.

In various embodiments, the implant can have a diameter. In some cases, the diameter of the implant can be about 0.1 mm to about 1.5 mm. In some cases, the diameter of the implant can be from about 0.7 mm to about 1.3 mm. In some cases, the diameter of the implant can be from about 0.9 mm to about 1.1 mm. In some cases, the diameter of the implant is at least about 0.1 mm, such as at least about 0.1 mm, at least about 0.2 mm, at least about 0.3 mm, at least about 0.4 mm, at least about 0.5 mm, at least about 0.6 mm, at least about 0.7 mm, at least about 0.8 mm, at least about 0.9 mm, at least about 1.0 mm, at least about 1.1 mm, at least about 1.2 mm, at least about 1.3 mm, at least about 1. 4 mm, or at least about 1.5 mm. In some cases, the diameter of the implant is less than about 1 mm, such as less than about 1 mm, less than about 0.9 mm, less than about 0.8 mm, less than about 0.7 mm, less than about 0.6 mm, less than about 0.5 mm, It can be less than about 0.4 mm, less than about 0.3 mm, less than about 0.2 mm, or less than about 0.1 mm. In some cases, the diameter of the implant can be at least about 0.1 mm. In some cases, the diameter of the implant can be at least about 0.8 mm. In some cases, the diameter of the implant can be about 1 mm.

In various embodiments, the implant can have a length. In some cases, the length of the implant can be about 1 mm to about 30 mm. In some cases, the length of the implant can be about 5 mm to about 25 mm. In some cases, the length of the implant can be about 10 mm to about 20 mm. In some cases, the length of the implant can be about 12 mm to about 18 mm. In some cases, the length of the implant is at least about 1 mm, at least about 2 mm, at least about 3 mm, at least about 4 mm, at least about 5 mm, at least about 6 mm, at least about 7 mm, at least about 8 mm, at least about 9 mm, at least about 10 mm. , at least about 11 mm, at least about 12 mm, at least about 13 mm, at least about 14 mm, at least about 15 mm, at least about 16 mm, at least about 17 mm, at least about 18 mm, at least about 19 mm, at least about 20 mm, at least about 21 mm, at least about 22 mm, at least It can be about 23 mm, at least about 24 mm, at least about 25 mm, at least about 26 mm, at least about 27 mm, at least about 28 mm, at least about 29 mm, or at least about 30 mm. In some cases, the length of the implant is at least about 1 mm. In some cases, the length of the implant is at least about 3 mm. In some cases, the length of the implant is approximately 15 mm. In some cases, the length of the implant is less than about 30 mm, such as less than about 30 mm, less than about 29 mm, less than about 28 mm, less than about 27 mm, less than about 26 mm, less than about 25 mm, less than about 24 mm, less than about 23 mm, about Less than 22 mm, less than about 21 mm, less than about 20 mm, less than about 19 mm, less than about 18 mm, less than about 17 mm, less than about 16 mm, less than about 15 mm, less than about 14 mm, less than about 13 mm, less than about 12 mm, less than about 11 mm, less than about 10 mm , less than about 9 mm, less than about 8 mm, less than about 7 mm, less than about 6 mm, less than about 5 mm, less than about 4 mm, less than about 3 mm, less than about 2 mm, or less than about 1 mm.

In various embodiments, the implant can have a volume. In some cases, the volume of the implant can be about 0.1 mm ³ to about 30 mm ³ . For example, the volume of the implant can be about 0.1 mm ³ , about 0.5 mm ³ , about 1 mm ³ , about 5 mm 3 , about 10 mm ³ , about 15 mm ³ , about 20 mm ³ , about 25 ^{mm 3 ,} or about 30 mm ³ . In some cases, the volume of the implant can be approximately 10 ^mm3 .

In various embodiments, the implant may lack a coating, covering, or sheath. For example, in some cases, a portion of the external surface of the implant is exposed directly to the biological environment (e.g., target tissue, biological fluids) after implantation, such that the external surface of the uncoated or uncovered portion of the implant is directly exposed to the biological environment (e.g., target tissue, biological fluids). It may be coated or uncoated so that it is coated or in direct contact. In some embodiments, the entire or substantially the entire outer surface of the implant is such that the entire or substantially the entire outer surface of the implant is directly exposed to or in direct contact with the biological environment after implantation. Uncoated or uncoated. In other cases, less than the entire external surface of the implant is directly exposed to or in direct contact with the biological environment after implantation. For example, in some cases at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the biological directly exposed to or in direct contact with the environment. In some cases, at least about 50% of the external surface of the implant is directly exposed to or in direct contact with the biological environment after implantation. In some cases, the implant may lack a sheath, scaffold, retention member, retention frame, or any other additional means for retaining the implant within the target tissue. In some cases, the implant may consist essentially of a polymeric matrix and a therapeutically active agent (eg, apalutamide) dispersed therein.

In some cases, the implant may include a coating. In some cases, a coating may cover the implant. In some cases, the coating may partially cover the implant. In some cases, the coating may substantially cover the implant. In some cases, the implant may include a core made of a first polymeric material and a coating of a second polymeric material. In a non-limiting example, an implant of the present disclosure may include a non-silicone core surrounded by a silicone coating. In some cases, implants of the present disclosure are metal-free. In some cases, the coating is biodegradable. In other cases, the coating is non-biodegradable.

In various embodiments, the implant may prevent modulation of the apalutamide it contains when the implant is implanted in a subject. Modulation may include, but is not limited to, degradation, chemical modulation, and the like. For example, the biological environment of a tissue may contain degradants (eg, esterases, amidases) that can degrade the drug. In some cases, the implant may protect the therapeutically active agent from degradation by preventing degradation products from entering the implant. In various embodiments, in vitro stability studies may be performed to determine the protective effects of the implant on the therapeutically active agents contained therein. In such cases, the therapeutically active agent may be able to diffuse out of the implant while maintaining in vivo stability within the implant. In various embodiments, the ability of a degradant to degrade a therapeutically active agent within an implant can be determined by a simulated in vivo stability assay. In a non-limiting example, an implant of the present disclosure containing a therapeutically active agent can be incubated in a solution containing degradants (which are known to degrade therapeutically active agents). After a period of incubation, the therapeutically active agent can be extracted from the implant and the degradation peak can be measured (eg, by high performance liquid chromatography (HPLC)).

In various aspects of the present disclosure, the implants of the present disclosure may be configured to be delivered directly to a target tissue of a subject. In some cases, the target tissue can be prostate tissue. In some cases, the implants of the present disclosure may be configured to be delivered to tissue adjacent to or near the target tissue. In some cases, the therapeutically active agent can diffuse out of the implant in a controlled manner and act directly on the target tissue.

In various aspects, the implants of the present disclosure can be configured to remain within the target tissue for a period of time. In some cases, the implants of the present disclosure may be configured to remain within the target tissue indefinitely (eg, never removed). In some cases, more than one implant of the present disclosure may be implanted into a target tissue. For example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more than 20 implants are targeted. can be implanted into tissue. In some cases, two or more implants may be implanted at different sites in the target tissue (eg, to deliver drugs to different sites in the target tissue). In some cases, two or more implants may be implanted in close proximity to each other within the target tissue. In some cases, one or more initial implants may be implanted, and additional implants may be implanted later after the drug is depleted from the initial implant. For example, one or more additional implants can be implanted after the drug has stopped or substantially stopped eluting from one or more initial implants. In some cases, the implants of the present disclosure may be ultrasound visible when disposed within the target tissue of a subject. In such cases, the position of the implant can be monitored non-invasively. In some cases, the implant may be sterilized prior to implantation into the subject. In some cases, the implant is sterilized by gamma sterilization.

In various embodiments, the implants of the present disclosure may be capable of delivering sustained release of apalutamide over a period of time. For example, implants of the present disclosure may be capable of sustained release of apalutamide. "Sustained release" as used herein refers to the ability of an implant to release a fixed amount of drug over an extended period of time after implantation into the target tissue. In some cases, the implants of the present disclosure deliver an amount (e.g., a therapeutically effective amount) of a drug to a target tissue for at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 18 months. or at least 24 months. In some cases, the implants of the present disclosure can deliver a fixed amount (eg, a therapeutically effective amount) of a drug to a target tissue for up to two years. In certain cases, the implants of the present disclosure deliver at least 0.1 μg/day of apalutamide for at least 6 months after implantation into the target tissue (e.g., prostate tissue or tissue adjacent to or near the prostate). may be possible. In some cases, implants of the present disclosure provide at least 0.1 μg/day of apalutamide for up to 24 months (e.g., , to the prostate).

Methods for Manufacturing Drug Implants Further provided herein are methods for manufacturing the implants described herein. Non-limiting examples of methods for manufacturing drug implants of the present disclosure may be as provided in Example 1 and Example 2.

In some embodiments, the method may include mixing an amount of uncured polymeric material with an amount of apalutamide to form a mixture. In some cases, the polymer is a thermoset and apalutamide is mixed into the uncured polymeric material. In some cases, the polymer is thermoplastic and the apalutamide is mixed into the solution or melt of the polymeric material. The method may further include shaping the mixture to produce a shaped structure. The molded structure may be formed by forming the mixture in a mold (eg, a transfer molding process), by extruding the mixture (eg, through a tube), or by any other process. For thermosets, the method may further include curing the shaped mixture for a period of time with or without elevated temperatures. In some cases, the polymeric material can be any biocompatible silicone provided herein. In an exemplary embodiment, the silicone can be Silbione® ADH1 M200. In the case of thermoplastics, the mixture can be shaped as described at elevated temperatures and cooled to solidify the polymer. In some cases, the thermoplastic resin can be any biocompatible polyurethane provided herein.

In some embodiments, the mixture can further include a solvent. Non-limiting examples of solvents that may be used include pentane, heptane, toluene, dichloromethane, tetrahydrofuran, and hexane. Solvents can be used, for example, to reduce the viscosity of liquid polymers. In some embodiments, the mixture can be formed by a transfer molding process or by extrusion (eg, through a tube).

The therapeutically active agent (e.g., apalutamide) is present in an implant where the total amount of active agent in the implant is from about 0.5% w/w to about 70% w/w, such as about 0.5% w/w, about 1% w. /w, about 5% w/w, about 10% w/w, about 15% w/w, about 20% w/w, about 25% w/w, about 30% w/w, about 35% w/w w, about 40% w/w, about 45% w/w, about 50% w/w, about 55% w/w, about 60% w/w, about 65% w/w, or about 70% w/w w may be provided in the mixture. In some cases, the total amount of active agent (e.g., apalutamide) in the implant is at least about 0.5% w/w, at least about 1% w/w, at least about 5% w/w, at least about 10% w/w. /w, at least about 15% w/w, at least about 20% w/w, at least about 25% w/w, at least about 30% w/w, at least about 35% w/w, at least about 40% w/w , at least about 45% w/w, at least about 50% w/w, at least about 55% w/w, at least about 60% w/w, at least about 65% w/w, or at least about 70% w/w. could be. Apalutamide can be provided in the mixture in an amount such that the total amount of apalutamide in the implant can be from about 1 mg to about 10 mg.

In some embodiments, the thermoforming is from about 150°C to about 200°C, such as about 150°C, about 155°C, about 160°C, about 165°C, about 170°C, about 175°C, about 180°C, about 185°C. C., about 190.degree. C., about 195.degree. C., or about 200.degree. C., including heating and shaping the mixture (eg, transfer molding, extrusion, or another process). Molding temperature generally depends on the polymer material selected. Generally, the molding temperature of the polymeric material is selected to be lower than the melting temperature of the therapeutically active agent. In the case of thermoplastics, the mixture is heated for a sufficient time to achieve a moldable state prior to molding. In some cases, the mixture is heated for about 3 minutes to about 8 minutes, such as about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, or about 8 minutes. In some cases, the melting temperature of apalutamide (eg, about 190° C. to about 192° C.) may be higher than the molding temperature of the silicone.

In some embodiments, the mixture may further include a solvent. Non-limiting examples of solvents that may be used include pentane, heptane, toluene, dichloromethane, tetrahydrofuran, and hexane. Solvents can be used, for example, to reduce the viscosity of liquid polymers. In some embodiments, the mixture can be formed by a transfer molding process or by extrusion (eg, through a tube).

After manufacturing the implant as provided herein, the method may further include performing one or more analyzes on the implant. In some cases, the one or more analyzes can be differential scanning calorimetry (DSC) (eg, to determine the rate of hardening of the implant and/or to evaluate properties of the drug). In some cases, the one or more analyzes can be placement of the implant in replacement tissue. In some cases, the one or more analyzes can be a dissolution test (eg, to assess the rate of dissolution of the drug from the implant). In some cases, the one or more analyzes can be an in vivo stability test (eg, to assess the ability of the degradant to penetrate the implant). In some cases, the one or more analyzes can be viscometry. In some cases, the one or more analyzes can be the use of a rheometer (eg, to assess the viscosity and cure profile of the formulation). In some cases, the one or more analyzes can be high pressure liquid chromatography (eg, to confirm content uniformity and evaluate impurities in drug formulations and shaped implants). In some cases, the one or more analyzes can be dynamic mechanical analysis (DMA) (eg, to evaluate the mechanical properties of the implant to ensure that it can be placed correctly).

Methods of Treatment Disclosed herein are methods of treating a disease (or symptoms thereof) in a subject. The terms "treating,""therapy," or "treating" are used interchangeably herein and may refer to providing therapeutic benefit to a subject in need thereof. For example, treating a disease or disorder includes ameliorating, inhibiting, reducing, alleviating, or curing the disease or disorder. Treating a disease or disorder also includes ameliorating, suppressing, reducing, alleviating, or curing one or more symptoms associated with the disease or disorder. When used in relation to a tumor, treating includes shrinking or reducing the size of the tumor or tumor volume.

In various embodiments, the subject may have been diagnosed with the disease, may be suspected of having the disease, or may be at risk of having the disease (one or more symptoms thereof). In some cases, the method includes implanting an implant of the present disclosure into a target tissue of the subject. Implants of the present disclosure may be implanted into target tissue by any method. In some cases, the implant may be implanted into the target tissue by surgical or non-surgical methods. In some cases, the implant may be implanted using standard surgical tools, such as those commonly used for biopsies or brachytherapy. In some cases, the implant can be implanted into the target tissue by using, for example, a needle, forceps, or a catheter (eg, with a lumen). For example, in one embodiment, the implant may be implanted into the target tissue by placement through the lumen of a needle or catheter. In some cases, the implant may be implanted into the target tissue using the cannula of a prostate biopsy needle. In some cases, the implant may be implanted into the target tissue using a Mick® needle. In some cases, implant placement may be guided by ultrasound. In some cases, the implant may be implanted by transperineal implantation (eg, by use of a template-guided needle). In some cases, the implant may be sterilized and placed within packaging.

In a non-limiting example, a method of placing an implant of the present disclosure in a target tissue can include placing a distal end of an elongate tube in the target tissue (eg, the prostate or tissue adjacent to the prostate). In some cases, the elongated tube can be a needle with a lumen. The elongate tube can have a sharp end so that the distal end of the elongate tube can penetrate the target tissue. In some cases, the distal end of the elongate tube may be disposed through a first portion of the grid (eg, a guide template) such that a first position of the elongate tube in the subject is determined. The grid may allow for proper placement of the implant in the target tissue. In some cases, the trocar is disposed within the lumen of the elongated tube. The method may include inserting an elongate tube into the target tissue (with or without a trocar disposed within the lumen of the elongate tube). If a trocar is used, the method may further include removing the trocar from the lumen of the elongate tube while maintaining the distal end of the elongate tube within the target tissue. The method may further include placing an implant of the present disclosure within the lumen of the elongate tube. The implant may be pushed through the lumen of the elongated tube with a blunt ended rod (eg, a stylet) sized to fit within the lumen of the elongated tube. A stylet can be used to push the implant from the proximal end of the elongated tube to the distal end of the elongated tube. The method may further include removing the elongated tube from the target tissue while maintaining the stylet in place. Once the elongate tube is removed from the target tissue, the stylet can force the implant from the elongate tube and into the target tissue. The method may further include removing both the stylet and the elongated tube together from the target tissue.

In some embodiments, the method may include implanting more than one implant in the target tissue of the subject. For example, the method may include implanting a first implant in a first portion of target tissue and implanting a second implant in a second portion of target tissue. In some cases, the first portion of target tissue and the second portion of target tissue may be different. In some cases, a first implant can include a first therapeutically active agent (eg, apalutamide) and a second implant can include a second therapeutically active agent. In some cases, the first therapeutically active agent and the second therapeutically active agent can be the same. In other cases, the first therapeutically active agent (eg, apalutamide) and the second therapeutically active agent may be different. In some cases, a grid (e.g., a guide template) may be used to position a first implant within a first portion of target tissue and a second implant within a second portion of target tissue. can. In some cases, the first implant and/or the second implant may be positioned using ultrasound guidance.

In some embodiments, the method may further include implanting an additional implant into the target tissue. For example, the method includes implanting a third implant into a third portion of the target tissue, implanting a fourth implant into a fourth portion of the target tissue, and implanting a fifth implant into a fifth portion of the target tissue. implanting a sixth implant into a sixth portion of the target tissue; implanting a seventh implant into a seventh portion of the target tissue; implanting an eighth implant into a seventh portion of the target tissue; 8, and the like. Each of the third, fourth, fifth, sixth, seventh, eighth, or more therapeutically active agents may be the same, different, or a combination thereof. In some cases, at least three implants are implanted into the target tissue. For example, at least three implants can be implanted into the prostate or into tissue adjacent or proximate to the prostate by transperineal administration.

In some embodiments, one or more implants may be implanted into the prostate or into tissue adjacent or proximate to the prostate prior to a surgical procedure to treat prostate cancer. For example, one or more implants may be implanted in the prostate or in tissue adjacent or proximate to the prostate prior to performing a prostatectomy (eg, one week, two weeks, three weeks, etc.). In such cases, prostatectomy may remove the prostate gland or a portion thereof. In some cases, prostatectomy may remove one or more of the implants from the subject. In other cases, one or more implants may be implanted into the prostate or into tissue adjacent or proximate to the prostate and remain within the prostate indefinitely. For example, one or more implants may provide a therapeutically effective amount of apalutamide to prostate tissue for a period of time, such as when a subject is in remission or healing of prostate cancer.

The term "subject" as used herein generally refers to a vertebrate, such as a mammal, eg, a human. Mammals include, but are not limited to, mice, monkeys, humans, research animals, farm animals, sports animals, and pets. In some cases, the methods described herein can be used on tissues derived from a subject and the progeny of such tissues. Tissue can be obtained in vivo from a subject. In some cases, tissues may be cultured in vitro.

In some embodiments, the methods provided herein can be used to treat a subject in need of treatment. In some cases, the subject may be suffering from a disease. In some cases, the subject can be human. In some cases, the human may be a patient in a hospital or clinic. In some cases, the subject can be a non-human animal, such as a non-human primate, a domestic animal, a domestic pet, or a laboratory animal. For example, non-human animals include apes (e.g., chimpanzees, baboons, gorillas, or orangutans), Old World monkeys (e.g., rhesus macaques), New World monkeys, dogs, cats, bison, camels, cows, deer, pigs, donkeys, It can be a horse, mule, llama, sheep, goat, buffalo, reindeer, yak, mouse, rat, rabbit, or any other non-human animal.

If the subject can be a human, the subject can be of any age. In some cases, the subject can be about 50 years of age or older. In some cases, the subject can be about 55 years of age or older. In some cases, the subject can be about 60 years of age or older. In some cases, the subject can be about 65 years of age or older. In some cases, the subject can be about 70 years of age or older. In some cases, the subject can be about 75 years of age or older. In some cases, the subject can be about 80 years of age or older. In some cases, the subject can be about 85 years of age or older. In some cases, the subject can be about 90 years old or older. In some cases, the subject can be about 95 years of age or older. In some cases, the subject can be about 100 years old or older. In some cases, the subject is approximately 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63 years old. , 64 years old, 65 years old, 66 years old, 67 years old, 68 years old, 69 years old, 70 years old, 71 years old, 72 years old, 73 years old, 74 years old, 75 years old, 76 years old, 77 years old, 78 years old, 79 years old, 80 years old years old, 81 years old, 82 years old, 83 years old, 84 years old, 85 years old, 86 years old, 87 years old, 88 years old, 89 years old, 90 years old, 91 years old, 92 years old, 93 years old, 94 years old, 95 years old, 96 years old, It can be 97 years old, 98 years old, 99 years old, 100 years old, or over 100 years old. In some cases, the subject is approximately 1 year old, 2 years old, 3 years old, 4 years old, 5 years old, 6 years old, 7 years old, 8 years old, 9 years old, 10 years old, 11 years old, 12 years old, 13 years old, 14 years old , 15 years old, 16 years old, 17 years old, 18 years old, 19 years old, 20 years old, or over 20 years old

In some cases, the methods provided herein can treat a disease in a subject. In some cases, the methods provided herein can alleviate or reduce symptoms of a disease. In some cases, the methods provided herein can result in a reduction in the severity of one or more symptoms associated with a disease. In some cases, the methods provided herein can slow, halt, or reverse the progression of one or more symptoms associated with a disease. In some cases, the methods provided herein can prevent the occurrence of one or more symptoms associated with a disease. In some cases, the methods provided herein can slow, halt, or reverse disease progression as measured by the number and severity of symptoms experienced.

In some cases, the disease can be a proliferative disease or disorder. In some cases, the proliferative disease or disorder may be cancer. In some cases, the subject may have a tumor. In some cases, this method may reduce tumor size. In some cases, the method reduces the size of the tumor by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least It can be reduced by about 95% or about 100%.

In some embodiments, the proliferative disease or disorder can be a prostatic proliferative disease or disorder. In one non-limiting example, the proliferative disease or disorder of the prostate can be prostate cancer. Prostate cancer can be an adenocarcinoma, a sarcoma, a neuroendocrine tumor, a small cell carcinoma, a transitional cell carcinoma, or a squamous cell carcinoma. In another non-limiting example, the proliferative disease or disorder of the prostate can be benign prostatic hyperplasia.

This method can be utilized to deliver therapeutically effective amounts of drugs to target tissues. In some cases, the method may include delivering a drug implant to a target tissue (or tissue adjacent to the target tissue) of the subject. Any tissue may be suitable for delivery of the drug implants of the present disclosure. In an exemplary case, the target tissue may be the prostate, tissue adjacent to the prostate, or both. Non-limiting examples of target tissues include breast, pancreas, bladder, brain, skin, kidneys, lungs, liver, tongue, esophagus, stomach, intestines, gallbladder, heart, pituitary gland, pineal gland, thyroid, parathyroid glands. These include the adrenal glands, eyes, bones, fallopian tubes, uterus, ovaries, sinuses, inner ear (eustachian tubes), testes, and cervix.

In various aspects of the present disclosure, a method for implanting a drug implant of the present disclosure into a target tissue (or adjacent tissue) of a subject, wherein the implant delivers a therapeutically effective amount of a drug to the target tissue. I will provide a. As used herein, "therapeutically effective amount" when used in reference to a drug or therapeutically active agent refers to an amount of the drug or therapeutically active agent that is capable of eliciting a therapeutic response in a subject. In various embodiments of the present disclosure, the implant can deliver a therapeutically effective amount of drug to a subject's tissue for a period of 3 to 24 months. In some cases, the implant delivers a therapeutically effective amount of drug to the target tissue at 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, Delivery may be for a period of 1 month, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, or 24 months. In some cases, the implant delivers a therapeutically effective amount of the drug to the target tissue for at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months. , at least 11 months, at least 12 months, at least 13 months, at least 14 months, at least 15 months, at least 16 months, at least 17 months, at least 18 months, at least 19 months, at least 20 months, at least 21 months, at least 22 months, at least It may be delivered for 23 months, or at least 24 months. In various embodiments, the drug implant is configured to deliver a therapeutically effective amount of apalutamide to the desired treatment site for up to two years.

In various embodiments of the present disclosure, a therapeutically effective amount of drug can be at least about 0.1 μg/day. In some cases, the therapeutically effective amount of the drug is at least about 0.1 μg/day, about 0.2 μg/day, about 0.3 μg/day, about 0.4 μg/day, about 0.5 μg/day, about 0 .6μg/day, about 0.7μg/day, about 0.8μg/day, about 0.9μg/day, about 1μg/day, about 2μg/day, about 3μg/day, about 4μg/day, about 5μg/day , about 6 μg/day, about 7 μg/day, about 8 μg/day, about 9 μg/day, about 10 μg/day, about 15 μg/day, about 20 μg/day, about 25 μg/day, about 30 μg/day, about 35 μg/day , about 40 μg/day, about 45 μg/day, about 50 μg/day, about 55 μg/day, about 60 μg/day, about 65 μg/day, about 70 μg/day, about 75 μg/day, about 80 μg/day, about 85 μg/day , about 90 μg/day, about 95 μg/day, about 100 μg/day, about 110 μg/day, about 120 μg/day, about 130 μg/day, about 140 μg/day, about 150 μg/day, about 160 μg/day, about 170 μg/day , about 180 μg/day, about 190 μg/day, about 200 μg/day, about 210 μg/day, about 220 μg/day, about 230 μg/day, about 240 μg/day, about 250 μg/day, about 260 μg/day, about 270 μg/day , about 280 μg/day, about 290 μg/day, about 300 μg/day, about 310 μg/day, about 320 μg/day, about 330 μg/day, about 340 μg/day, about 350 μg/day, about 360 μg/day, about 370 μg/day , about 380 μg/day, about 390 μg/day, about 400 μg/day, about 410 μg/day, about 420 μg/day, about 430 μg/day, about 440 μg/day, about 450 μg/day, about 460 μg/day, about 470 μg/day , about 480 μg/day, about 490 μg/day, about 500 μg/day, about 510 μg/day, about 520 μg/day, about 530 μg/day, about 540 μg/day, about 550 μg/day, about 560 μg/day, about 570 μg/day , about 580 μg/day, about 590 μg/day, about 600 μg/day, about 610 μg/day, about 620 μg/day, about 630 μg/day, about 640 μg/day, about 650 μg/day, about 660 μg/day, about 670 μg/day , about 680 μg/day, about 690 μg/day, about 700 μg/day, about 710 μg/day, about 720 μg/day, about 730 μg/day, about 740 μg/day, about 750 μg/day, about 760 μg/day, about 770 μg/day , about 780 μg/day, about 790 μg/day, about 800 μg/day, about 810 μg/day, about 820 μg/day, about 830 μg/day, about 840 μg/day, about 850 μg/day, about 860 μg/day, about 870 μg/day , about 880 μg/day, about 890 μg/day, about 900 μg/day, about 910 μg/day, about 920 μg/day, about 930 μg/day, about 940 μg/day, about 950 μg/day, about 960 μg/day, about 970 μg/day , about 980 μg/day, about 990 μg/day, about 1000 μg/day or more. It is understood that a therapeutically effective amount of a drug can vary based on the drug and/or disease being treated and can be determined empirically.

In various embodiments, the implant can result in cumulative release of apalutamide from the implant to the target tissue. In some cases, the cumulative in vitro release of apalutamide from the implant can be at least 10 μg on day 1. In some cases, the in vitro cumulative release of apalutamide from the implant can be at least 100 μg at day 60. In some cases, the in vitro cumulative release of apalutamide from the implant can be at least 150 μg at day 120. In some cases, at least 50% of the total amount of apalutamide present within the implant at the time of implantation remains within the polymer matrix 100 days after implantation.

In various embodiments, the implant is 2,000 μg or less by day 1, 10,000 μg or less by day 60, and/or 12,000 μg or less by day 120, and at least The cumulative release of apalutamide in the in vitro model may be 10 μg, at least 100 μg by day 60, and/or at least 150 μg by day 120. In some cases, in vitro models involve incubating drug implants in 1% sodium dodecyl sulfate (SDS) in water with continuous agitation at 37°C (see Example 4).

In various aspects of the present disclosure, the implant may be configured to remain within the target tissue for a period of time. In some cases, the implant can be configured to remain in the target tissue for an extended period of time (eg, months to years) or indefinitely (eg, can never be removed). For example, after the implant has delivered all of the therapeutically active agent contained therein to the subject, the implant (free of therapeutically active agent) may remain within the target tissue. In some cases, if additional treatment is required, one or more additional implants may be delivered to the target tissue (without removing the initial implant). In some cases, implants are non-biodegradable, non-bioabsorbable, and/or non-bioerodible such that the polymeric material remains substantially intact within the target tissue for extended periods or indefinitely. It may be constructed from a polymeric material.

Advantageously, the implants of the present disclosure are capable of delivering a therapeutically effective amount of apalutamide to prostate tissue or tissue adjacent or proximate to the prostate for an extended period of time (eg, at least 3 months). Furthermore, the implant of the present disclosure can deliver high concentrations of apalutamide locally to the prostate while maintaining low systemic concentrations of apalutamide. In some cases, implants of the present disclosure may reduce or prevent toxicity due to low systemic concentrations of apalutamide.

In various embodiments, the total dose of apalutamide administered to a subject by an implant of the present disclosure is less than the total dose of apalutamide when administered to a subject by systemic (eg, oral) administration. A standard oral regimen of apalutamide includes 240 mg/day apalutamide monotherapy for prostate cancer. Advantageously, the implants of the present disclosure provide administration of a lower total dose of apalutamide compared to oral administration regimens. In some cases, the total amount of bicalutamide administered to the subject is less than 100 mg over a six month period.

In various embodiments, implantation of a drug implant of the present disclosure into the prostate gland or into tissue adjacent or proximate to the prostate gland results in plasma concentrations of apalutamide obtained when apalutamide is administered to a subject by systemic (e.g., oral) administration. This results in plasma concentrations of apalutamide that are substantially lower than . For example, the steady state plasma concentration of apalutamide (assuming a daily dose of 240 mg) has been reported to be approximately 6 μg/ml. In some cases, implants of the present disclosure, when implanted in the prostate or tissue adjacent or proximate to the prostate, result in steady state plasma concentrations of apalutamide of less than 6 μg/ml.

Kits Further provided herein are kits. In some embodiments, a kit can include one or more implants as described herein. For example, the kit may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 20 pieces. May contain many implants. In some cases, one or more implants may include a therapeutically active agent contained therein. In some cases, each of the one or more implants can include apalutamide. In other cases, each of the one or more implants may contain one or more different therapeutically active agents.

In some embodiments, the kit may include one or more surgical tools such as needles or forceps. In some embodiments, the kit can be packaged in a sterile package. In some cases, sterile packaging includes foil. In some embodiments, the kit can further include instructions for implanting the implant into the tissue of a subject (eg, for treating a disease or condition as described herein).

Specific Terminology Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. It is to be understood that the foregoing summary and the following detailed description are merely exemplary and explanatory and are not intended to limit any claimed subject matter.

In this application, the use of the singular includes the plural unless specifically stated otherwise. As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Please note that. In this application, the use of "or" means "and/or" unless stated otherwise. Furthermore, the use of the term "including" and other forms such as "include," "includes," and "included" is not limiting.

As used herein, ranges and amounts can be expressed as "about" a particular value or range. About also includes exact amounts. Therefore, "about 5 μL" also means "about 5 μL" and "5 μL." Generally, the term "about" includes amounts that would be expected to be within experimental error, such as within 15%, 10% or 5%.

The section headings used herein are for organizational purposes only and are not to be construed as limitations on the subject matter described.

Example 1. Methods for Making Implants The manufacture of implants involves the formulation of an active pharmaceutical ingredient (API) (e.g. apalutamide) with an elastomer (e.g. acetoxy-cured silicone) to ensure homogeneous mixing of the API within the polymer matrix. It involves two main steps: preparation and shaping of the implant to ensure that the product can be placed in the organ as intended.

Formulation The implant formulation includes medical grade silicone as an excipient mixed with the API. Optionally, use a solvent to reduce the viscosity of the silicone to incorporate the desired API loading.

Apalutamide formulations are made using a centrifugal mixer. Add the required amount of silicone to a mixing cup and add an equal weight of a solvent (which dissolves the silicone; for example, pentane). The silicone and solvent are mixed at high speed until the viscosity of the silicone is reduced so that the silicone flows. The API powder is then incorporated into a mixing cup and mixed at high speed until a visually smooth mixture with no dry API spots is obtained. The solvent is then removed under vacuum, leaving a paste of silicone and API. A portion of the solvent (up to 50% w/w) can be left in the mixture to slow the curing process, extend pot life, and reduce viscosity to aid molding or extrusion. Table 1 below shows an example of a formulation of apalutamide made at a loading of 10% by weight.

Other methods to achieve the same mixing uniformity with less solvent may be used, such as shear mixing. Other solvents that help reduce viscosity and dissolve the silicone, such as dichloromethane, tetrahydrofuran, hexane, pentane, heptane, toluene, etc., may also be used in the formulation.

Molding Implant rods are made using (eg, aluminum) molds (eg, via a transfer molding process) or by extruding the apalutamide formulation (eg, through a tube). The molded rod is cured at a specified temperature (approximately 25° C.±5° C.) for a predetermined time (3-8 minutes) based on the silicone supplier's curing recommendations. After curing, the mold is cooled and the rod is separated from the mold for characterization.

Example 2. Method for Making the Implant In this example, the implant formulation includes thermoplastic polyurethane as an excipient mixed with the API.

Formulation A solvent is used to dissolve the polyurethane to allow it to combine with the API and produce a uniform dispersion with the desired loading. After compounding, the solvent is removed and the resulting polyurethane-API pellets are formed into implant rods by transfer molding or extrusion.

The polyurethane pellets are added to a mixing cup with a solvent (eg dichloromethane) and incubated at 37° C. with stirring for several hours until dissolution of the polyurethane is achieved. The ratio of polyurethane to solvent is selected to achieve complete dissolution of the polyurethane with a solution of sufficiently low viscosity (eg, about 20% solids content by weight) to be mixed. The API powder is then added to the solvent and mixed at high speed until a visibly smooth mixture with no dry API spots is obtained. Table 2 below shows an example of a formulation made with 30% API w/w. The solvent is then removed under vacuum, leaving a large pellet of polyurethane, API, and residual solvent that can be used for thermoforming. Table 3 below provides an exemplary set of solvent removal conditions. Other solvents that dissolve the polyurethane, such as tetrahydrofuran, dimethylformamide, dimethylacetamide, etc., may also be used in the formulation.

Molding Implant rods are made using (eg, aluminum) molds (eg, via a transfer molding process) or by extruding the apalutamide formulation (eg, through a tube). The formulation is melted at a specific temperature (approximately 150° C.-200° C.) for several minutes (approximately 3-8 minutes) before injection or extrusion. After curing, the mold is cooled and the rod is separated from the mold for characterization.

Example 3. Characterization of Apalutamide-Containing Formulations and Implants Various analytical techniques are used to characterize formulations and shaped implants. For example, differential scanning calorimetry (DSC) is used to determine the hardening rate of implants and evaluate drug properties. A dissolution test is used to assess the rate of drug dissolution from the implant. For example, high pressure liquid chromatography (HPLC) is used to confirm content uniformity and evaluate impurities in drug formulations and molded rods.

Example 4. Evaluation and Characterization of Drug Implants Containing Apalutamide Multiple formulation candidates containing apalutamide were tested.

Table 1 below shows the various polymer matrices tested.

Several formulations were made using apalutamide (multiple sources - R&D grade and GMP grade). All formulations were formed into 1 mm diameter and 5 mm length rods for testing via dissolution and DSC. Table 2 below shows the different formulations tested.

Elkem200 process:
Single piece acetoxy cured silicone. It hardens in the presence of ambient moisture, releasing acetic acid as a by-product. When exposed to air, the "takt time" was approximately 20 minutes. Approximately 24 hours are required for complete curing.

A solvent was used to thin the silicone and prevent premature curing. However, although pentane was tested, other applicable solvents such as tetrahydrofuran and dichloromethane can be used. API powder was mixed with silicone and solvent in a SpeedMixer. A portion of the solvent was removed under vacuum, leaving about 10-30% by weight of solvent depending on pot life and viscosity. The uncured mixture was extruded into PTFE tubes and allowed to harden for 12 hours at room temperature before separation.

Figures 1A and 1B show the results of elution tests performed on silicone implants containing apalutamide at various loading levels. Briefly, implants were incubated at 37°C in a stirred solution of 1% sodium dodecyl sulfate (SDS) in water. Apalutamide elution was estimated by sampling the solution and replacing the apalutamide concentration measured via HPLC at various time points. Figures 1A and 1B show that by varying the apalutamide loading in the silicone matrix, a range of apalutamide release levels can be achieved. FIG. 1A shows the cumulative release of apalutamide from silicone implants over time. FIG. 1B shows the release rate of apalutamide from the silicone implant over time.

Figure 2 shows the results of dissolution testing of silicone implants containing 10% w/w apalutamide with and without pentane solvent and with different apalutamide sources. The dissolution test conditions were as described above for FIGS. 1A and 1B. Figure 2 shows that there was minimal difference in elution of apalutamide by addition of pentane solvent or different sources of apalutamide.

Figures 3A and 3B show differential scanning calorimetry (DSC) results for silicone implants containing 10% w/w apalutamide. Figure 3A shows the DSC of a silicone implant containing 10% w/w apalutamide and pentane mixture. Figure 3B shows DSC of a silicone implant containing 10% w/w apalutamide, hand mixing. Minimal changes in apalutamide melting when formulated in silicone + pentane did not suggest changes in crystallinity.

Lubrizol TPU process:
Excipient grade "Pathway" product line from Lubrizol (PY-PT87AS). The TPU pellet was dissolved in dichloromethane (DCM) at 37°C. Apalutamide powder was mixed into TPU-DCM using a SpeedMixer. DCM was removed under vacuum to reform solid TPU+apalutamide. A transfer press was used to melt and form the rod into an implant rod.

Figures 4A and 4B show the results of elution tests performed on TPU implants. Briefly, implants were incubated at 37°C in a stirred solution of 1% sodium dodecyl sulfate (SDS) in water. The solution was sampled and replaced at various time points and apalutamide concentration was measured via HPLC to estimate apalutamide elution. Figures 4A and 4B show that by varying the apalutamide loading in the TPU matrix, a range of apalutamide release levels can be achieved. FIG. 4A shows the cumulative release of apalutamide from TPU implants over time at various loading amounts of apalutamide. FIG. 4B shows the release rate of apalutamide from the TPU implant over time at various loadings of apalutamide.

Figure 5 shows the predicted release rate of a drug implant containing TPU and 70% w/w apalutamide in an in vitro system of 1% SDS in water and stirred and incubated at 37°C. A 70% w/w formulation of apalutamide in a TPU implant is expected to release drug in vitro for up to 125 days.

Figures 6A and 6B show differential scanning calorimetry (DSC) results for formulations containing TPU and 10% w/w apalutamide. Figure 6A shows the DSC of TPU+10% w/w apalutamide mixture. Figure 6B shows the DSC of molded TPU+10% w/w apalutamide. No peaks were seen in the thermograms of either formulation suggesting that the apalutamide became and remained amorphous throughout the process.

Figures 7A and 7B show differential scanning calorimetry (DSC) results for formulations containing TPU and 70% w/w apalutamide. Figure 7A shows the DSC of TPU+70% w/w apalutamide mixture. Figure 7B shows the DSC of molded TPU+70% w/w apalutamide. Apalutamide melting peaks were seen in both thermograms, and a large peak was observed in the formed rods suggesting recrystallization during the forming process.

Claims (60)

A drug implant comprising a mixture of a non-biodegradable, non-bioabsorbable, and/or non-bioerodible polymer and apalutamide, wherein said drug implant is implanted in a subject and releases said apalutamide to a desired treatment site. A drug implant configured to: 2. The drug implant of claim 1, wherein the drug implant is configured to release a therapeutically effective amount of the apalutamide to the desired treatment site. 3. The drug implant of claim 2, wherein the drug implant is configured to release the therapeutically effective amount of the apalutamide to the desired treatment site for at least 3 months. 4. The drug implant of claim 2 or 3, wherein the drug implant is configured to release the therapeutically effective amount of the apalutamide to the desired treatment site for at least 6 months. A drug implant according to any one of claims 2 to 4, wherein the drug implant is configured to release the therapeutically effective amount of the apalutamide into the desired treatment site for up to two years. The cumulative release of apalutamide in the in vitro model is 2,000 μg or less by day 1, 10,000 μg or less by day 60, and/or 12,000 μg or less by day 120, and by day 1 at least 10 μg by day 60, and/or at least 150 μg by day 120, and the in vitro model was prepared using 1% sodium dodecyl sulfate (SDS) in water with continuous stirring at 37°C. A drug implant according to any one of the preceding claims, comprising incubating said drug implant in said drug implant. 6. The drug implant of any one of the preceding claims, wherein the drug implant releases at least 0.1 micrograms/day of the apalutamide 6 months after implantation in the subject. 7. The drug implant of any one of the preceding claims, wherein at least 50% of the total apalutamide remains in the drug implant 100 days after implantation into the subject. Drug implant according to any one of the preceding claims, wherein the apalutamide is present in the drug implant in an amount of at least 10% w/w. Drug implant according to any one of the preceding claims, wherein the apalutamide is present in the drug implant in an amount of at least 30% w/w. Drug implant according to any one of the preceding claims, wherein the apalutamide is present in the drug implant in an amount of at least 50% w/w. Drug implant according to any one of the preceding claims, wherein the apalutamide is present in the drug implant in an amount of at least 70% w/w. Drug implant according to any one of the preceding claims, wherein the apalutamide is present in the drug implant in an amount of 10% to 70% w/w. The drug implant of any one of the preceding claims, wherein the drug implant has a Shore A hardness of at least 25 durometers when loaded with 10% apalutamide. The drug implant according to any one of the preceding claims, wherein the non-biodegradable, non-bioabsorbable and/or non-bioerodible polymer comprises silicone. 16. The drug implant of claim 15, wherein the silicone is an acetoxy cured silicone. Drug implant according to any one of the preceding claims, wherein the non-biodegradable, non-bioabsorbable and/or non-bioerodible polymer comprises thermoplastic polyurethane (TPU). The drug implant of any one of the preceding claims, wherein the total amount of apalutamide in the drug implant is about 1 mg to about 20 mg. The drug implant according to any one of the preceding claims, wherein the non-biodegradable, non-bioabsorbable and/or non-bioerodible polymer is biocompatible. The preceding claim, wherein at least 99% of the non-biodegradable, non-bioabsorbable, and/or non-bioerodible polymer is configured to remain in the target tissue of a subject for at least 600 days after implantation. A drug implant according to any one of paragraphs. Drug implant according to any one of the preceding claims, wherein the apalutamide is in solid form. A drug implant according to any one of the preceding claims, wherein at least a portion of the apalutamide is in crystalline form. 7. The drug implant of any one of the preceding claims, wherein the drug implant is ultrasound visible when disposed in a target tissue of a subject. The drug implant according to any one of the preceding claims, wherein the apalutamide has a melting temperature higher than the molding or curing temperature of the non-biodegradable, non-bioabsorbable and/or non-bioerodible polymer. 7. The drug implant of any one of the preceding claims, wherein the drug implant inhibits modulation of the apalutamide within the drug implant. 26. The drug implant of claim 25, wherein said modulation comprises degradation. 7. A drug implant according to any one of the preceding claims, wherein the drug implant is elongated. 7. A drug implant according to any one of the preceding claims, wherein the drug implant is cylindrical. 7. A drug implant according to any one of the preceding claims, wherein the drug implant is tubular. A drug implant according to any one of the preceding claims, wherein the drug implant is rod-shaped. The drug implant of any one of the preceding claims, wherein the drug implant has a diameter of about 0.1 mm to about 1.5 mm. The drug implant of any one of the preceding claims, wherein the length of the drug implant is about 1 mm to about 30 mm. The drug implant according to any one of the preceding claims, wherein the volume of the drug implant is about 0.1 mm ³ to about 30 mm ³ . 7. A drug implant according to any preceding claim, wherein at least 50% of the outer surface of the drug implant is configured for direct contact with target tissue. 7. A drug implant according to any one of the preceding claims, wherein the desired treatment site is the prostate or prostate tissue. 7. A drug implant according to any preceding claim, wherein the drug implant is configured to be delivered to the subject using a needle or catheter lumen. The drug according to any one of the preceding claims, wherein the drug implant lacks at least one of a sheath, a scaffold, a retention member, or a combination thereof to retain the drug implant within a target tissue. implant. 7. The drug implant of any one of the preceding claims, wherein the drug implant further comprises a coating. 39. The drug implant of claim 38, wherein the coating partially covers the drug implant. 39. The drug implant of claim 38, wherein the coating substantially covers the drug implant. 39. The drug implant of claim 38, wherein the coating covers the drug implant. Drug implant according to any one of claims 38 to 41, wherein the coating is biodegradable. Drug implant according to any one of claims 38 to 41, wherein the coating is non-biodegradable. 7. A drug implant according to any one of the preceding claims, wherein the drug implant is sterile. 7. A drug implant according to any one of the preceding claims, wherein the drug implant is arranged in a sterilizable package. 2. The drug implant of claim 1, consisting essentially of the non-biodegradable, non-bioabsorbable, and/or non-bioerodible polymer and the apalutamide. 47. A method of treating a proliferative disease of the prostate in a subject, said method comprising administering one or more drug implants according to any one of claims 1 to 46 to prostate tissue or tissue near the prostate of said subject. A method, including porting to. 48. The method of claim 47, wherein the one or more drug implants deliver a therapeutically effective amount of the apalutamide to the prostate for at least 3 months. 49. The method of claim 47 or 48, wherein the one or more drug implants deliver a therapeutically effective amount of the apalutamide to the prostate for at least 6 months. 50. The method according to any one of claims 47 to 49, wherein the proliferative disease of the prostate is prostate cancer or benign prostatic hyperplasia. 51. A method according to any one of claims 47 to 50, wherein the apalutamide is dispersed within the non-biodegradable, non-bioabsorbable and/or non-bioerodible polymer prior to the implantation. 52. Any one of claims 47-51, wherein said implanting comprises placing each of said one or more drug implants into said prostate tissue or tissue near said prostate through a lumen of a needle or catheter. The method described in section. 53. The method according to any one of claims 47 to 52, wherein said implantation is performed by transperineal administration. 54. The method of any one of claims 47-53, wherein said transperineal administration comprises using a template guided needle. 55. The method of any one of claims 47-54, wherein the total dose of apalutamide administered to the subject is less than the total dose of apalutamide when administered to the subject by oral administration. 56. The method of any one of claims 47-55, wherein the total dose of apalutamide administered to the subject is less than 200 mg over a period of 6 months. 57. The method of any one of claims 47-56, wherein said transplantation results in a plasma concentration of apalutamide that is less than the plasma concentration of apalutamide obtained when apalutamide is administered to the subject by oral administration. 58. The method of any one of claims 47-57, wherein said transplantation results in a subtherapeutic steady state plasma concentration of apalutamide. 57. The method of any one of claims 45-56, wherein the one or more drug implants comprises 2 to 20 drug implants. It is a kit,
A sterilizable package comprising a drug implant according to any one of claims 1 to 46;
and instructions for implanting the drug implant into a target tissue of a subject.

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